- Email: [email protected]
Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone
Increased Incidence of Hip Fractures in Dialysis Patients With Low Serum Parathyroid Hormone Maria Coco, MD, and Heather Rush, MD ● To study the complications of renal osteodystrophy in patients with end-stage renal disease, we reviewed the incidence of hip fractures in our outpatient dialysis population from 1988 to 1998. One thousand two hundred seventy-two patients were treated for a total of 4,039 patient-years; 56 hip fractures were documented during this period. The incidence of hip fractures was many times greater in the dialysis patients than in the general population in each of the age-, race-, and sex-matched subgroups. The 1-year mortality rate from the hip fracture event was nearly two and a half times greater in the dialysis patients compared with the general population. The incidence of hip fractures in the first half of the decade was similar to that observed in the second half. When parathyroid hormone (PTH) levels were evaluated, we determined that patients with lower serum PTH levels were more likely to sustain a hip fracture than patients with higher PTH levels (P < 0.006). In addition, we determined that patients with lower PTH levels had an earlier mortality than patients with higher PTH levels (P < 0.03). We conclude that despite more aggressive therapy directed toward bone health in our dialysis patients in recent years, the incidence of hip fractures and their devastating morbidity and mortality remained unchanged over the past decade. Lower PTH levels may predispose to earlier mortality. © 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Hip fracture; parathyroid hormone (PTH); renal osteodystrophy; dialysis.
H
IP FRACTURES serve as an index of bone health in the general population. Because nearly every hip fracture results in hospitalization, the incidence of such fractures in various subsets of the general population can be easily characterized. Incidence varies with sex,1 race,1 and country of origin.2,3 In the United States, hip fractures are more prevalent in women than men4,5 and in whites than blacks.6-10 The morbidity and mortality associated with hip fractures have been well established in the general population.5,7,10,11 There has been a concerted effort to identify risk factors for bone disease in the general population and address the specific causes in an attempt to reduce the incidence of hip fractures.11 Patients with end-stage renal disease (ESRD) develop renal osteodystrophy from various causes, including hyperparathyroidism, 12,13 adynamic bone disease,14,15 and aluminum bone toxicity.12-17 Although causes of hip fractures in the general population have been elucidated, few published data examine the incidence and characteristics of hip fractures in the dialysis population. Vertebral fractures in dialysis patients have correlated with low bone mineral density in some studies,18 but not in others.19 Vitamin K deficiency in dialysis patients has also been correlated with increased risk for bone fractures.20,21 Data published in abstract form examined discharge diagnoses in a Medicare hospitalization database and found an
increased incidence of hip fractures in patients with ESRD.22 In light of the limited published information, we examined the incidence and characteristics of hip fractures that occurred in our outpatient dialysis patients between 1988 and 1998. METHODS
Patient Selection Hospital admission lists and medical records of all patients treated for at least 6 months at the outpatient dialysis unit affiliated with Montefiore Medical Center (Bronx, NY) between 1988 and 1998 were carefully reviewed; 1,272 patients were thus reviewed. A hip fracture, limited to the intertrochanteric and proximal femoral neck region, was defined as an event diagnosed by radiology. Pathological fractures secondary to metastatic malignancies were excluded. The patients’ average age (defined as the sum of the age each year on dialysis therapy divided by the number of years on dialysis therapy), race, sex, cause of ESRD, and time on dialysis were recorded. Averaged values over the course of the dialysis period for intact parathyroid hormone (PTH), calcium, ionized calcium, phosphorus, serum alkaline phosphatase, aluminum, and albumin for the entire cohort of dialysis patients were
From Montefiore Medical Center, Bronx, NY. Received February 4, 2000; accepted in revised form July 14, 2000. Address reprint requests to Maria Coco, MD, Montefiore Medical Center, 111 East 210th St, Bronx, New York 10467. E-mail: [email protected] © 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3606-0003$3.00/0 doi:10.1053/ajkd.2000.19812
American Journal of Kidney Diseases, Vol 36, No 6 (December), 2000: pp 1115-1121
1115
1116
COCO AND RUSH Table 1.
Patient Demographics and Distribution of Patients by Age and Sex Total Dialysis Population
Fracture Patients
1,272
56
608 (49) 664 (51)
19 (34) 37 (66)
621 (49) 409 (32) 223 (18) 19 (1)
25 (45) 12 (21) 19 (34) —
467 (39) 224 (18) 360 (30) 39 (3) 115 (10)
22 (39) 11 (20) 13 (23) 6 (11) 4 (7)
Total no. of patients Sex Men Women Race Black Hispanic White Other Cause of ESRD DM CGN Nephrosclerosis APKD Other Total
Men
Women
Total
Men
Women
Age (y)
58 ⫾ 0.4*
56.3 ⫾ 0.4*
58.4 ⫾ 0.8*
62.5 ⫾ 2.0†‡
64.4 ⫾ 3.6†§
61.4 ⫾ 3.6†㛳
10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
3 48 123 188 262 300 215 98 6
1 22 50 112 135 129 90 46 2
2 23 73 76 127 170 125 52 4
— — 3 8 14 11 11 9 —
— — 1 3 3 4 3 5 —
— — 2 5 11 7 8 4 —
NOTE. Values expressed as number (percent) or mean ⫾ SEM unless otherwise noted. Abbreviations: DM, diabetes mellitus; CGN, chronic glomerulonephritis; APKD, adult polycystic kidney disease. * Averaged age. † Age at fracture. ‡ P ⬍ 0.001 versus patients without hip fracture. § P ⬍ 0.001 versus male patients without hip fracture. 㛳 P ⬍ 0.001 versus female patients without hip fracture.
determined. Chemistry test results of patients who sustained a hip fracture were included only up to the time of the fracture. Chemistry tests were performed monthly, except for PTH, which was measured on a quarterly basis. Patients were divided into four groups based on their average intact PTH values. Group 1 included patients with PTH values less than 65 pg/dL. Group 2 represented the treatment goal group, with PTH levels up to three times the upper limit of normal (PTH, 66 to 195 pg/dL). Group 3 included patients with PTH values between 196 and 500 pg/dL; and group 4 included patients with severely elevated PTH values (⬎500 pg/dL). A total of 6,767 PTH values in patients were averaged and distributed into these groups. One-year mortality rate from the time of hip fracture was determined by reviewing medical records and compared with mortality rates of the dialysis patients who did not sustain a hip fracture. These data were also compared with published age- and sex-matched data on hip fractures in the general population.
Statistics Data are presented as mean ⫾ SEM. Standardized ratios were calculated by the indirect method of standardization, and confidence intervals were determined using Poisson distribution.23,24 Fracture-free survival and patient survival curves were plotted by the estimation method of Kaplan and Meier. The log-rank test was used to compare survival curves from different groups. A Cox proportional hazards model was used to analyze the effects of covariates on fracture-free survival and patient survival rates. The impact of covariates on survival was first tested with univariate analysis. Only those covariates significant by univariate analysis were used in multivariate analyses. The covariates tested were sex, race, age, total duration of dialysis, cause of ESRD, and values for serum calcium, ionized calcium, phosphorus, alkaline phosphatase, aluminum, albumin, and intact PTH. Statistical significance is defined as P less than 0.05.
HIP FRACTURES AND LOW PTH
RESULTS
Dialysis Population One thousand two hundred seventy-two patients received treatment between 1988 and 1998, for a total of 4,039 patient-years. Demographics are listed in Table 1. Forty-nine percent of the patients were men, 51% were women, 49% were black, 32% were Hispanic, and 18% were white. Because of the small number of patients in other racial groups (1%), other racial groups were not considered further. Fifty-six of these patients sustained a hip fracture during this time. There was no significant difference in the cause of ESRD in patients who fractured a hip compared with those who did not. The number of patients distributed in each age decade is listed in Table 1. Patients who sustained a hip fracture were significantly older than those who did not sustain a hip fracture (P ⬍ 0.001). There was no difference in time on dialysis therapy between the patients with and without a fracture. The demographics of our dialysis population did not change significantly with respect to race, age, and sex between 1988 and 1998. Hip Fracture Incidence Fifty-six hip fractures were recorded during the period under study. The incidence of hip fractures in our dialysis patients is expressed as the number of fractures per 1,000 patient-years and is compared with age-, sex-, and racematched published data for the general population in the United States (Table 2). A standardized fracture ratio (SFR: observed fractures in our dialysis patients per 1,000 patient-years divided by the expected fractures in the general population per 1,000 patient-years) was calculated with a 95% confidence interval for each ratio. The SFR was many times greater in the dialysis patients than in the general population for each age, sex, and race subgroup (Table 2). The incidence of fractures in our dialysis population was 13.9/1,000 patient-years, with an SFR 17.4 times greater than that in the general population. Male dialysis patients had an SFR 14.2 times greater than that of men in the general population, whereas women dialysis patients had an SFR 17.2 times greater than that of women in the general population. We evaluated SFRs in the three racial groups
1117 Table 2. Hip Fracture Incidence and SFR in Our Dialysis Patients Compared With the General US Population
Total Men Total Black Hispanic White Black men Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 Hispanic men Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 White men Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 Women Total Black Hispanic White Black women Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 Hispanic women Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 White women Age (y) 30-39 40-49 50-59 60-69 70-79 80-89
Incidence*
SFR†
95% CI (for SFR)
13.9
17.4
12.4-34.0
11.7 11.9 5.2 30.3
14.2 6.6 5.4 7.7
9.3-28.6 3.5-11.7 1.7-12.0 5.1-10.8
10.9 10.8 5.8 13.0 9.9 50.3
28.0 24.5 20.7 11.9 5.2 8.6
14.1-50.6 12.5-44.7 7.9-46.6 6.4-20.4 2.5-9.7 4.3-7.7
— 8.1 5.6 6.5 — —
— ‡ 37.3 19.1 — —
— 14.7-87.1 8.3-42.4 — —
— — 47.4 — 50.9 94.5
— — 47.8 — 15.2 7.8
— — 34.8-63.0 — 11.4-20.1 6.4-9.6
24.1 16.5 18.7 55.2
17.2 7.7 8.5 5.7
7.1-19.4 4.6-12.7 5.2-13.5 4.3-7.4
18.5 9.3 32.6 5.3 17.1 —
192.7 76.9 59.3 4.3 7.5 —
165.9-220.4 34.0-141.2 47.4-92.7 1.3-9.5 4.3-11.9 —
— 25.7 18.1 28.4 18.4 —
— ‡ 113.1 47.3 7.4 —
— 66.7-158.2 31.0-67.5 4.3-9.8 —
— 175.0 68.5 30.2 71.2 57.1
— 134.6 117.5 11.4 14.0 5.4
— 112.4-146.7 92.0-149.8 7.6-16.1 10.9-17.6 4.1-7.0
Abbreviation: CI, confidence interval. * Fractures per 1,000 patient-years. † Observed fractures/expected fractures per 1,000 patient-years. ‡ SFR not calculated: incidence rates not reported in US general population.
1118
COCO AND RUSH
and found that they were greater in each group compared with the general population (Table 2). The incidence of fracture was greater in women dialysis patients (24.1/1,000 patient-years) than in men dialysis patients (11.7/1,000 patientyears), similar to that reported in the general population. Of note, the average age at the time of hip fracture in our ESRD population was 64.4 ⫾ 3.6 years in men dialysis patients compared with 80 years among men sustaining fractures in the general population and 61.4 ⫾ 3.6 years in women dialysis patients compared with 74 years in women with fractures in the general population.25 Although the SFR in the dialysis patients remained elevated compared with the general population throughout the decades, it decreased with increasing age in all race and sex subgroups (Table 2). Variables Predicting Hip Fractures Using univariate analysis, it was determined that sex, race, age, levels of phosphorus, alkaline phosphatase, and albumin, and the groups designated by intact PTH level were significant variables differentiating the patients with hip fractures from those without hip fractures. By means of multivariate analysis using Cox regression, using race, sex, and the groups designated by intact PTH level as categorical variables and age and phosphorus, alkaline phosphatase, and albumin levels as covariates, we found that white race, age, greater alkaline phosphatase levels, and PTH values less than 195 pg/dL significantly predicted fractures. Patients in the subgroups with greater PTH levels did not have an increased risk for developing a hip fracture (Table 3). A life-table analysis comparing the risk for hip Table 3. Multivariate Analysis by Cox Regression Analysis for Factors Predicting Fractures in the Dialysis Population Variable
White race Age Alkaline phosphatase Albumin PTH ⬍195 pg/dL
R
Exp B
95% CI
P
0.1416 0.1688
4.3765 1.0584
1.7-11.6 1.03-1.1
0.003 0.001
0.2202 ⫺0.1451 0.1281
1.0025 0.2955 5.8215
1.0-1.01 0.14-0.65 1.7-20
0.001 0.002 0.006
Abbreviation: CI, confidence interval.
Fig 1.
Effect of PTH level on fracture.
fracture among the subgroups designated by PTH values in our entire dialysis population between 1988 and 1998 was constructed (Fig 1). The risk for fracture was greater in the group of patients with lower serum PTH levels than in the patients with higher PTH values (P ⬍ 0.006). Mortality Rates One-year mortality from the hip fracture event was evaluated. The overall 1-year mortality rate after hip fracture in dialysis patients was 64% compared with the 1-year mortality rate of 20% reported in the general population. One-year mortality rates in our dialysis patients were 61% for men and 42% for women. Reported 1-year mortality rates after hip fracture in the general population were 36% for men and 21% for women. One-year mortality rates per 1,000 patientyears were determined in our patients with and without hip fractures. Standardized mortality rates (SMR: observed death rate over the expected death rate in the reference population) were then calculated for the dialysis patients with hip fractures versus those without hip fractures and versus the rates reported for the general population with hip fractures. The SMR was 2.7 times greater in the dialysis patients with hip fractures compared with the dialysis patients without hip fractures and 2.4 times greater than that in the general population with hip fractures (Table 4). Male patients with hip fractures had a mortality rate 3.6 times greater than that of the rest of the
HIP FRACTURES AND LOW PTH Table 4.
One-Year Mortality Rates per 1,000 Patient-Years
MR MR (No Hip (Hip Fracture) Fracture)
Total Men ⬍65 y ⬎65 y Women ⬍65 y ⬎65 y
1119
177.1 160.3 158.0 259.0 194.1 158.0 253.8
482 579 111.1 1,000.0 432 476 375
SMR (95% CI)*
SMR (95% CI)†
2.7 (1.4-4) 2.4 (1.2-3.6) 3.6 (1.4-5.8) 1.6 (0.7-20) 0.7 (0.5-0.9) 3.9 2.2 (1.2-3.7) 2.2 (1.1-3.4) 3.1 (1-5.5) 1.5 (1.36-1.7)
Abbreviations: MR, mortality rates; SMR, standardized mortality rate; CI, confidence interval. * Dialysis patients with versus without hip fracture. † Dialysis patients with hip fracture versus general population with hip fracture.
male dialysis population, whereas the SMR comparing them with the general population was 1.6 times greater. Of note, the 1-year mortality rate of all our elderly male patients with hip fractures was 100%. Women patients with hip fractures had a 2.2 times greater mortality rate than the patients without hip fractures and the general female population with hip fractures. The effect of PTH values on survival in the entire dialysis population during the period studied was examined using life-survival analysis. Survival in patients with lower PTH values was shorter than that in patients with higher PTH values (P ⬍ 0.03; Fig 2). By means of Cox regression analysis, using sex, race, PTH subgroups, and values for alkaline phosphatase, phos-
Fig 2. Effect of PTH level on survival in the entire dialysis population.
Table 5. Multivariate Analysis by Cox Regression Analysis for Factors Predicting Death in the Dialysis Population Variable
PTH ⬍195 pg/dL Phosphorus Albumin Average age
R
Exp B
95% CI
P
0.0273 0.0569 ⫺0.1571 0.1199
1.4384 1.1751 0.2480 1.0334
1.1-2.0 1.1-1.3 0.19-0.33 1.0-1.1
0.03 0.001 0.001 0.001
Abbreviation: CI, confidence interval.
phorus, and albumin as covariates, it was determined that phosphorus level and lower PTH values impacted negatively on survival, whereas a greater albumin level and younger age impacted positively on survival (Table 5). There was no significant difference in the average age of the reference dialysis population in the first half of the decade (57.7 ⫾ 0.6 years) compared with the second half (57.9 ⫾ 0.5 years). The fracture incidence in the first half of the decade was compared with that in the second half; total hip fracture incidence was calculated at 158.8/1,000 patient-years from 1988 to 1993 and 155.2/1,000 patient-years from 1994 to 1998. There was no significant difference between the rates. DISCUSSION
The incidence of hip fractures is well characterized in the general population. The incidence varies with race,8,9,26 sex,1,2,25,27 and country of origin.9,28 Greater rates are found in the northernmost Scandinavian countries,27 whereas rates are much less in countries closer to the equator.27,29 Reported rates in the United States also vary according to race, sex, and location. However, in general, greater rates for hip fracture are reported in women than men and in whites than blacks.3 Few studies have evaluated the rate in the Hispanic population.30 Our study shows similar trends with respect to sex and race in the dialysis population; however, the rates in our dialysis patients are magnified many fold. The overall incidence of hip fractures in the dialysis population was 17.4 times greater than that in the general population (Table 2). The hip fracture incidence in men in our dialysis population was 11.7/1,000 patient-years, an incidence 14.2 times greater than that in the general male population. The hip fracture rate in women in our dialysis population was 24.1/1,000 patient-
1120
years, 17.2 times greater than that reported in the general female population. Analyzed by race, we found that although white patients had the greatest incidence of hip fracture in the dialysis population, black and Hispanic patients also had a much greater incidence than their age- and sex-matched counterparts in the general population.30 Thus, the sex and race distribution of hip fractures in our dialysis population follows a pattern similar to that seen in the general population; however, the rates are magnified many times. Another finding of interest is that age at the time of fracture in our cohort of dialysis patients was 64.4 ⫾ 3.6 years in men and 61.4 ⫾ 3.6 years in women compared with 80 and 74 years in the general population.5,7,30 Thus, dialysis patients sustained hip fractures at an age 11 to 15 years younger than their counterparts in the general population. Compared with the reference dialysis population, patients who sustained hip fractures were significantly older than those who did not (Table 1), suggesting the contribution of such additional underlying age-related conditions as osteoporosis. It is interesting to note that the SFR, although remaining magnified compared with the general population, decreased with age in the dialysis patients. This may reflect a decreased activity level in elderly dialysis patients. The 1-year mortality rate after a hip fracture has been reported as 15% to 20% in the general US population,31 with 1-year mortality rates of 21% for women and 36% for men.25,28 In the study of our dialysis patients, we found a 1-year mortality rate of 64% after hip fracture, with 1-year mortality rates of 61% for men and 42% for women. When rates were standardized, the overall 1-year mortality rate after hip fracture in dialysis patients was 2.4 times greater than that found in the general population (Table 4). From our study, it is evident that lower PTH levels correlate with hip fractures, whereas higher PTH values do not predispose to hip fractures. It is interesting that the patients who had PTH values between 196 and 500 pg/dL showed a greater probability of fracture than the group with PTH values greater than 500 pg/dL. This group probably represents a mixture of adynamic bone disease and hyperparathyroid bone disease,32 thus resulting in a greater fracture rate than the group with almost certain hyperparathy-
COCO AND RUSH
roid bone disease. Histologically, very low PTH levels correlated well with adynamic bone disease,14,15,32 which theoretically predisposes to bone fractures in renal osteodystrophy.15,32 It therefore is possible that oversuppression of PTH, resulting in adynamic bone disease, may predispose to hip fractures in dialysis patients. Other studies found a correlation between vertebral fractures and low PTH values in dialysis patients.18,19 Serum aluminum levels were not significantly different in the fracture versus nonfracture groups and did not correlate with occurrence of hip fracture. However, because bone biopsies were not systematically performed, we cannot exclude a contribution from aluminum bone disease. Diabetes mellitus may also affect bone histological characteristics, giving rise to adynamic bone disease.15,33 Patients with diabetes composed 38% of our fracture population, similar to the reference dialysis population. There was no significant difference in cause of ESRD between the fracture and nonfracture groups; therefore, it is unlikely that diabetes mellitus was a major factor predisposing to fractures in the dialysis population. By life-table analysis, we show that survival rate may be influenced by average PTH levels. Lower PTH levels predispose to early mortality in the general dialysis population. A correlation between low PTH level at the start of renal replacement therapy and subsequent early mortality has been reported.34 The duration of dialysis in the entire cohort of patients who sustained hip fractures was not significantly longer than that in the reference dialysis population In this regard, no relation between duration of dialysis therapy and vertebral fracture rate in the Japanese male dialysis patient was found.21 A review of the patients’ chemistry test results showed no significant difference among the groups for calcium, ionized calcium, and aluminum levels. In addition, when the fracture incidence was compared over time, a similar incidence was found in the first half of the decade compared with the second half. In summary, we have shown that the incidence of hip fractures in a dialysis population is alarmingly high compared with that in the general population. The high incidence of hip fractures in patients with ESRD correlates with low PTH
HIP FRACTURES AND LOW PTH
values and likely adynamic bone disease. Oneyear mortality after hip fracture is greater in dialysis patients compared with dialysis patients without hip fracture and greater than that reported in the general population with hip fracture. Our data indicate that survival of patients with ESRD may also be adversely influenced by lower serum PTH levels. These findings suggest that the current practice of aggressive suppression of PTH may need to be revisited. Further studies are necessary to determine the optimum therapy of bone disease in the patient with ESRD. REFERENCES 1. Kellie S, Brody J: Sex-specific and race-specific hip fracture rates. Am J Public Health 80:326-328, 1990 2. Samsioe G: Osteoporosis—An update. Acta Obstet Gynecol Scand 76:189-199, 1997 3. Lindsay R, Cosman F: Primary osteoporosis, in Coe F, Favus M (eds): Disorders of Bone and Mineral Metabolism. New York, NY, Raven, 1992, pp 831-837 4. Jones D, Koval K, Zuckerman J, Aharonoff G, Skrovon M: Epidemiology, in Koval KJ, Zuckerman JD (eds): Fractures in the Elderly. Philadelphia, PA, LippincottRaven, 1998, pp 3-9 5. Melton L, Therneau T, Larson D: Long-term trends in hip fracture prevalence: The influence of hip fracture incidence and survival. Osteoporos Int 8:68-74, 1998 6. Tucci, J: Osteoporosis update. Med Health 81:169173, 1998 7. Prestwood KM, Kenny AM: Osteoporosis: Pathogenesis, diagnosis, and treatment in older adults. Clin Geriatr Med 14:577-599, 1998 8. Farmer M, White L, Brody J, Bailey K: Race and sex differences in hip fracture incidence. Am J Public Health 74:1374-1380, 1984 9. Villa ML, Nelson L: Race, ethnicity, and osteoporosis, in Osteoporosis. San Diego, CA, Academic, 1996, pp 435447 10. Cummings S, Browner W, Bauer D, Stone K, Ensrud K, Jamal S, Ettinger B: Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med 339:733-738, 1998 11. Slemenda C: Prevention of hip fractures: Risk factor modifications. Am J Med 103:S65-S73, 1997 (suppl 2A) 12. Sherrard D, Hercz G, Pei Y, Maloney NA, Greenwood C, Manuel A, Saiphoo C, Fenton SS, Segre GV: The spectrum of bone disease in end-stage renal failure—An evolving disorder. Kidney Int 43:436-442, 1993 13. Indridson O, Quarles L: Prevention and management of renal osteodystrophy in dialysis patients, in Bushinsky D (ed): Renal Osteodystrophy. Philadelphia, PA, LippincottRaven, 1998, pp 445-472 14. Sherrard D: Low turnover renal osteodystrophy, in Bushinsky D (ed): Renal Osteodystrophy. Philadelphia, PA, Lippincott-Raven, 1998, pp 305-316 15. Malluche H, Monier-Faugere MC: Risk of adynamic
1121
bone disease in dialyzed patients. Kidney Int 42:S62-S67, 1992 (suppl 38) 16. Sherrard D: Aluminum and renal osteodystrophy. Semin Nephrol 6:5-11, 1986 17. Pierides A, Edwards W, Cullum U, McCall J, Ellis H: Hemodialysis encephalopathy with osteomalacic fractures and muscle weakness. Kidney Int 18:115-124, 1980 18. Atsumi K, Kushida K, Yamazaki K, Shimizu S, Ohmura A, Inoue T: Risk factors for vertebral fractures in renal osteodystrophy. Am J Kidney Dis 33:287-293, 1999 19. Piraino B, Chen T, Cooperstein L, Segre G, Puschett J: Fracture and vertebral bone mineral density in patients with renal osteodystrophy. Clin Nephrol 30:57-62, 1988 20. Kohlmeier M, Saupe J, Shearer M, Schaefer K, Asmus G: Bone health of adult hemodialysis patients is related to vitamin K status. Kidney Int 51:1218-1221, 1997 21. Kohlmeier M, Saupe J, Schaefer K, Asmus G: Bone fracture history and prospective bone fracture risk of hemodialysis patients are related to apolipoprotein E genotype. Calcif Tissue Int 62:278-281, 1998 22. Gupta A, Kallenbach L, Divine G: Increased risk of hip fractures in US Medicare end-stage renal disease (ESRD) patients. J Am Soc Nephrol 8:552A, 1977 (abstr) 23. Gardner M, Altman D: Statistics with confidence. BMJ 59-60, 1989 24. Ingelfinger J, Mosteller F, Thibodeau L, Ware J: Biostatistics in Clinical Medicine. New York, NY, Macmillan, 1983 25. Cooper C: Southampton, United Kingdom: The crippling consequences of fractures and their impact on quality of life. Am J Med 103:S12-S19, 1997 (suppl 2A) 26. Grisso JA, Kelsey JL, Strom BL, O’Brien LA, Maislin G, LaPann K, Samelson L, Hoffman S, and The Northeast Hip Fracture Study Group: Risk factors for hip fracture in black women. N Engl J Med 330:1555-1560, 1994 27. Lips P: Amsterdam, The Netherlands: Epidemiology and predictors of fractures associated with osteoporosis. Am J Med 103:S3-S11, 1997 (suppl 2A) 28. Cooper C, Melton LJ: Magnitude and impact of osteoporosis and fractures, in Osteoporosis. San Diego, CA, 1996, pp 419-434 29. Jacobsen SJ, Goldberg J, Miles TP, Brody J, Stiers W, Rimm AA: Race and sex differences in mortality following fracture of the hip. Am J Public Health 82:1147-1150, 1992 30. Villa M: Ethnicity and skeletal health, in Marcus R (ed): Osteoporosis. Cambridge, MA, Blackwell Scientific, 1994, pp 125-145 31. Centers for Disease Control and Prevention: Report of the Surgeon General, US Department of Health and Human Services. CDC, Atlanta, GA, 1996 32. Qi Q, Faugere M, Geng Z, Malluche H: Predictive values of serum parathyroid hormone levels for bone turnover in patients on chronic maintenance dialysis. Am J Kidney Dis 26:622-631, 1995 33. Pei Y, Hercz G, Greenwood C, Segre G, Manuel A, Saiphoo C, Fenton S, Sherrard D: Renal osteodystrophy in diabetic patients. Kidney Int 44:159-164, 1993 34. Avram MM, Sreedhara R, Avram DK, Muchnick RA, Fein P: Enrollment parathyroid hormone level is a new marker of survival in hemodialysis and peritoneal dialysis therapy for uremia. Am J Kidney Dis 28:924-930, 1996
H
IP FRACTURES serve as an index of bone health in the general population. Because nearly every hip fracture results in hospitalization, the incidence of such fractures in various subsets of the general population can be easily characterized. Incidence varies with sex,1 race,1 and country of origin.2,3 In the United States, hip fractures are more prevalent in women than men4,5 and in whites than blacks.6-10 The morbidity and mortality associated with hip fractures have been well established in the general population.5,7,10,11 There has been a concerted effort to identify risk factors for bone disease in the general population and address the specific causes in an attempt to reduce the incidence of hip fractures.11 Patients with end-stage renal disease (ESRD) develop renal osteodystrophy from various causes, including hyperparathyroidism, 12,13 adynamic bone disease,14,15 and aluminum bone toxicity.12-17 Although causes of hip fractures in the general population have been elucidated, few published data examine the incidence and characteristics of hip fractures in the dialysis population. Vertebral fractures in dialysis patients have correlated with low bone mineral density in some studies,18 but not in others.19 Vitamin K deficiency in dialysis patients has also been correlated with increased risk for bone fractures.20,21 Data published in abstract form examined discharge diagnoses in a Medicare hospitalization database and found an
increased incidence of hip fractures in patients with ESRD.22 In light of the limited published information, we examined the incidence and characteristics of hip fractures that occurred in our outpatient dialysis patients between 1988 and 1998. METHODS
Patient Selection Hospital admission lists and medical records of all patients treated for at least 6 months at the outpatient dialysis unit affiliated with Montefiore Medical Center (Bronx, NY) between 1988 and 1998 were carefully reviewed; 1,272 patients were thus reviewed. A hip fracture, limited to the intertrochanteric and proximal femoral neck region, was defined as an event diagnosed by radiology. Pathological fractures secondary to metastatic malignancies were excluded. The patients’ average age (defined as the sum of the age each year on dialysis therapy divided by the number of years on dialysis therapy), race, sex, cause of ESRD, and time on dialysis were recorded. Averaged values over the course of the dialysis period for intact parathyroid hormone (PTH), calcium, ionized calcium, phosphorus, serum alkaline phosphatase, aluminum, and albumin for the entire cohort of dialysis patients were
From Montefiore Medical Center, Bronx, NY. Received February 4, 2000; accepted in revised form July 14, 2000. Address reprint requests to Maria Coco, MD, Montefiore Medical Center, 111 East 210th St, Bronx, New York 10467. E-mail: [email protected] © 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3606-0003$3.00/0 doi:10.1053/ajkd.2000.19812
American Journal of Kidney Diseases, Vol 36, No 6 (December), 2000: pp 1115-1121
1115
1116
COCO AND RUSH Table 1.
Patient Demographics and Distribution of Patients by Age and Sex Total Dialysis Population
Fracture Patients
1,272
56
608 (49) 664 (51)
19 (34) 37 (66)
621 (49) 409 (32) 223 (18) 19 (1)
25 (45) 12 (21) 19 (34) —
467 (39) 224 (18) 360 (30) 39 (3) 115 (10)
22 (39) 11 (20) 13 (23) 6 (11) 4 (7)
Total no. of patients Sex Men Women Race Black Hispanic White Other Cause of ESRD DM CGN Nephrosclerosis APKD Other Total
Men
Women
Total
Men
Women
Age (y)
58 ⫾ 0.4*
56.3 ⫾ 0.4*
58.4 ⫾ 0.8*
62.5 ⫾ 2.0†‡
64.4 ⫾ 3.6†§
61.4 ⫾ 3.6†㛳
10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
3 48 123 188 262 300 215 98 6
1 22 50 112 135 129 90 46 2
2 23 73 76 127 170 125 52 4
— — 3 8 14 11 11 9 —
— — 1 3 3 4 3 5 —
— — 2 5 11 7 8 4 —
NOTE. Values expressed as number (percent) or mean ⫾ SEM unless otherwise noted. Abbreviations: DM, diabetes mellitus; CGN, chronic glomerulonephritis; APKD, adult polycystic kidney disease. * Averaged age. † Age at fracture. ‡ P ⬍ 0.001 versus patients without hip fracture. § P ⬍ 0.001 versus male patients without hip fracture. 㛳 P ⬍ 0.001 versus female patients without hip fracture.
determined. Chemistry test results of patients who sustained a hip fracture were included only up to the time of the fracture. Chemistry tests were performed monthly, except for PTH, which was measured on a quarterly basis. Patients were divided into four groups based on their average intact PTH values. Group 1 included patients with PTH values less than 65 pg/dL. Group 2 represented the treatment goal group, with PTH levels up to three times the upper limit of normal (PTH, 66 to 195 pg/dL). Group 3 included patients with PTH values between 196 and 500 pg/dL; and group 4 included patients with severely elevated PTH values (⬎500 pg/dL). A total of 6,767 PTH values in patients were averaged and distributed into these groups. One-year mortality rate from the time of hip fracture was determined by reviewing medical records and compared with mortality rates of the dialysis patients who did not sustain a hip fracture. These data were also compared with published age- and sex-matched data on hip fractures in the general population.
Statistics Data are presented as mean ⫾ SEM. Standardized ratios were calculated by the indirect method of standardization, and confidence intervals were determined using Poisson distribution.23,24 Fracture-free survival and patient survival curves were plotted by the estimation method of Kaplan and Meier. The log-rank test was used to compare survival curves from different groups. A Cox proportional hazards model was used to analyze the effects of covariates on fracture-free survival and patient survival rates. The impact of covariates on survival was first tested with univariate analysis. Only those covariates significant by univariate analysis were used in multivariate analyses. The covariates tested were sex, race, age, total duration of dialysis, cause of ESRD, and values for serum calcium, ionized calcium, phosphorus, alkaline phosphatase, aluminum, albumin, and intact PTH. Statistical significance is defined as P less than 0.05.
HIP FRACTURES AND LOW PTH
RESULTS
Dialysis Population One thousand two hundred seventy-two patients received treatment between 1988 and 1998, for a total of 4,039 patient-years. Demographics are listed in Table 1. Forty-nine percent of the patients were men, 51% were women, 49% were black, 32% were Hispanic, and 18% were white. Because of the small number of patients in other racial groups (1%), other racial groups were not considered further. Fifty-six of these patients sustained a hip fracture during this time. There was no significant difference in the cause of ESRD in patients who fractured a hip compared with those who did not. The number of patients distributed in each age decade is listed in Table 1. Patients who sustained a hip fracture were significantly older than those who did not sustain a hip fracture (P ⬍ 0.001). There was no difference in time on dialysis therapy between the patients with and without a fracture. The demographics of our dialysis population did not change significantly with respect to race, age, and sex between 1988 and 1998. Hip Fracture Incidence Fifty-six hip fractures were recorded during the period under study. The incidence of hip fractures in our dialysis patients is expressed as the number of fractures per 1,000 patient-years and is compared with age-, sex-, and racematched published data for the general population in the United States (Table 2). A standardized fracture ratio (SFR: observed fractures in our dialysis patients per 1,000 patient-years divided by the expected fractures in the general population per 1,000 patient-years) was calculated with a 95% confidence interval for each ratio. The SFR was many times greater in the dialysis patients than in the general population for each age, sex, and race subgroup (Table 2). The incidence of fractures in our dialysis population was 13.9/1,000 patient-years, with an SFR 17.4 times greater than that in the general population. Male dialysis patients had an SFR 14.2 times greater than that of men in the general population, whereas women dialysis patients had an SFR 17.2 times greater than that of women in the general population. We evaluated SFRs in the three racial groups
1117 Table 2. Hip Fracture Incidence and SFR in Our Dialysis Patients Compared With the General US Population
Total Men Total Black Hispanic White Black men Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 Hispanic men Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 White men Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 Women Total Black Hispanic White Black women Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 Hispanic women Age (y) 30-39 40-49 50-59 60-69 70-79 80-89 White women Age (y) 30-39 40-49 50-59 60-69 70-79 80-89
Incidence*
SFR†
95% CI (for SFR)
13.9
17.4
12.4-34.0
11.7 11.9 5.2 30.3
14.2 6.6 5.4 7.7
9.3-28.6 3.5-11.7 1.7-12.0 5.1-10.8
10.9 10.8 5.8 13.0 9.9 50.3
28.0 24.5 20.7 11.9 5.2 8.6
14.1-50.6 12.5-44.7 7.9-46.6 6.4-20.4 2.5-9.7 4.3-7.7
— 8.1 5.6 6.5 — —
— ‡ 37.3 19.1 — —
— 14.7-87.1 8.3-42.4 — —
— — 47.4 — 50.9 94.5
— — 47.8 — 15.2 7.8
— — 34.8-63.0 — 11.4-20.1 6.4-9.6
24.1 16.5 18.7 55.2
17.2 7.7 8.5 5.7
7.1-19.4 4.6-12.7 5.2-13.5 4.3-7.4
18.5 9.3 32.6 5.3 17.1 —
192.7 76.9 59.3 4.3 7.5 —
165.9-220.4 34.0-141.2 47.4-92.7 1.3-9.5 4.3-11.9 —
— 25.7 18.1 28.4 18.4 —
— ‡ 113.1 47.3 7.4 —
— 66.7-158.2 31.0-67.5 4.3-9.8 —
— 175.0 68.5 30.2 71.2 57.1
— 134.6 117.5 11.4 14.0 5.4
— 112.4-146.7 92.0-149.8 7.6-16.1 10.9-17.6 4.1-7.0
Abbreviation: CI, confidence interval. * Fractures per 1,000 patient-years. † Observed fractures/expected fractures per 1,000 patient-years. ‡ SFR not calculated: incidence rates not reported in US general population.
1118
COCO AND RUSH
and found that they were greater in each group compared with the general population (Table 2). The incidence of fracture was greater in women dialysis patients (24.1/1,000 patient-years) than in men dialysis patients (11.7/1,000 patientyears), similar to that reported in the general population. Of note, the average age at the time of hip fracture in our ESRD population was 64.4 ⫾ 3.6 years in men dialysis patients compared with 80 years among men sustaining fractures in the general population and 61.4 ⫾ 3.6 years in women dialysis patients compared with 74 years in women with fractures in the general population.25 Although the SFR in the dialysis patients remained elevated compared with the general population throughout the decades, it decreased with increasing age in all race and sex subgroups (Table 2). Variables Predicting Hip Fractures Using univariate analysis, it was determined that sex, race, age, levels of phosphorus, alkaline phosphatase, and albumin, and the groups designated by intact PTH level were significant variables differentiating the patients with hip fractures from those without hip fractures. By means of multivariate analysis using Cox regression, using race, sex, and the groups designated by intact PTH level as categorical variables and age and phosphorus, alkaline phosphatase, and albumin levels as covariates, we found that white race, age, greater alkaline phosphatase levels, and PTH values less than 195 pg/dL significantly predicted fractures. Patients in the subgroups with greater PTH levels did not have an increased risk for developing a hip fracture (Table 3). A life-table analysis comparing the risk for hip Table 3. Multivariate Analysis by Cox Regression Analysis for Factors Predicting Fractures in the Dialysis Population Variable
White race Age Alkaline phosphatase Albumin PTH ⬍195 pg/dL
R
Exp B
95% CI
P
0.1416 0.1688
4.3765 1.0584
1.7-11.6 1.03-1.1
0.003 0.001
0.2202 ⫺0.1451 0.1281
1.0025 0.2955 5.8215
1.0-1.01 0.14-0.65 1.7-20
0.001 0.002 0.006
Abbreviation: CI, confidence interval.
Fig 1.
Effect of PTH level on fracture.
fracture among the subgroups designated by PTH values in our entire dialysis population between 1988 and 1998 was constructed (Fig 1). The risk for fracture was greater in the group of patients with lower serum PTH levels than in the patients with higher PTH values (P ⬍ 0.006). Mortality Rates One-year mortality from the hip fracture event was evaluated. The overall 1-year mortality rate after hip fracture in dialysis patients was 64% compared with the 1-year mortality rate of 20% reported in the general population. One-year mortality rates in our dialysis patients were 61% for men and 42% for women. Reported 1-year mortality rates after hip fracture in the general population were 36% for men and 21% for women. One-year mortality rates per 1,000 patientyears were determined in our patients with and without hip fractures. Standardized mortality rates (SMR: observed death rate over the expected death rate in the reference population) were then calculated for the dialysis patients with hip fractures versus those without hip fractures and versus the rates reported for the general population with hip fractures. The SMR was 2.7 times greater in the dialysis patients with hip fractures compared with the dialysis patients without hip fractures and 2.4 times greater than that in the general population with hip fractures (Table 4). Male patients with hip fractures had a mortality rate 3.6 times greater than that of the rest of the
HIP FRACTURES AND LOW PTH Table 4.
One-Year Mortality Rates per 1,000 Patient-Years
MR MR (No Hip (Hip Fracture) Fracture)
Total Men ⬍65 y ⬎65 y Women ⬍65 y ⬎65 y
1119
177.1 160.3 158.0 259.0 194.1 158.0 253.8
482 579 111.1 1,000.0 432 476 375
SMR (95% CI)*
SMR (95% CI)†
2.7 (1.4-4) 2.4 (1.2-3.6) 3.6 (1.4-5.8) 1.6 (0.7-20) 0.7 (0.5-0.9) 3.9 2.2 (1.2-3.7) 2.2 (1.1-3.4) 3.1 (1-5.5) 1.5 (1.36-1.7)
Abbreviations: MR, mortality rates; SMR, standardized mortality rate; CI, confidence interval. * Dialysis patients with versus without hip fracture. † Dialysis patients with hip fracture versus general population with hip fracture.
male dialysis population, whereas the SMR comparing them with the general population was 1.6 times greater. Of note, the 1-year mortality rate of all our elderly male patients with hip fractures was 100%. Women patients with hip fractures had a 2.2 times greater mortality rate than the patients without hip fractures and the general female population with hip fractures. The effect of PTH values on survival in the entire dialysis population during the period studied was examined using life-survival analysis. Survival in patients with lower PTH values was shorter than that in patients with higher PTH values (P ⬍ 0.03; Fig 2). By means of Cox regression analysis, using sex, race, PTH subgroups, and values for alkaline phosphatase, phos-
Fig 2. Effect of PTH level on survival in the entire dialysis population.
Table 5. Multivariate Analysis by Cox Regression Analysis for Factors Predicting Death in the Dialysis Population Variable
PTH ⬍195 pg/dL Phosphorus Albumin Average age
R
Exp B
95% CI
P
0.0273 0.0569 ⫺0.1571 0.1199
1.4384 1.1751 0.2480 1.0334
1.1-2.0 1.1-1.3 0.19-0.33 1.0-1.1
0.03 0.001 0.001 0.001
Abbreviation: CI, confidence interval.
phorus, and albumin as covariates, it was determined that phosphorus level and lower PTH values impacted negatively on survival, whereas a greater albumin level and younger age impacted positively on survival (Table 5). There was no significant difference in the average age of the reference dialysis population in the first half of the decade (57.7 ⫾ 0.6 years) compared with the second half (57.9 ⫾ 0.5 years). The fracture incidence in the first half of the decade was compared with that in the second half; total hip fracture incidence was calculated at 158.8/1,000 patient-years from 1988 to 1993 and 155.2/1,000 patient-years from 1994 to 1998. There was no significant difference between the rates. DISCUSSION
The incidence of hip fractures is well characterized in the general population. The incidence varies with race,8,9,26 sex,1,2,25,27 and country of origin.9,28 Greater rates are found in the northernmost Scandinavian countries,27 whereas rates are much less in countries closer to the equator.27,29 Reported rates in the United States also vary according to race, sex, and location. However, in general, greater rates for hip fracture are reported in women than men and in whites than blacks.3 Few studies have evaluated the rate in the Hispanic population.30 Our study shows similar trends with respect to sex and race in the dialysis population; however, the rates in our dialysis patients are magnified many fold. The overall incidence of hip fractures in the dialysis population was 17.4 times greater than that in the general population (Table 2). The hip fracture incidence in men in our dialysis population was 11.7/1,000 patient-years, an incidence 14.2 times greater than that in the general male population. The hip fracture rate in women in our dialysis population was 24.1/1,000 patient-
1120
years, 17.2 times greater than that reported in the general female population. Analyzed by race, we found that although white patients had the greatest incidence of hip fracture in the dialysis population, black and Hispanic patients also had a much greater incidence than their age- and sex-matched counterparts in the general population.30 Thus, the sex and race distribution of hip fractures in our dialysis population follows a pattern similar to that seen in the general population; however, the rates are magnified many times. Another finding of interest is that age at the time of fracture in our cohort of dialysis patients was 64.4 ⫾ 3.6 years in men and 61.4 ⫾ 3.6 years in women compared with 80 and 74 years in the general population.5,7,30 Thus, dialysis patients sustained hip fractures at an age 11 to 15 years younger than their counterparts in the general population. Compared with the reference dialysis population, patients who sustained hip fractures were significantly older than those who did not (Table 1), suggesting the contribution of such additional underlying age-related conditions as osteoporosis. It is interesting to note that the SFR, although remaining magnified compared with the general population, decreased with age in the dialysis patients. This may reflect a decreased activity level in elderly dialysis patients. The 1-year mortality rate after a hip fracture has been reported as 15% to 20% in the general US population,31 with 1-year mortality rates of 21% for women and 36% for men.25,28 In the study of our dialysis patients, we found a 1-year mortality rate of 64% after hip fracture, with 1-year mortality rates of 61% for men and 42% for women. When rates were standardized, the overall 1-year mortality rate after hip fracture in dialysis patients was 2.4 times greater than that found in the general population (Table 4). From our study, it is evident that lower PTH levels correlate with hip fractures, whereas higher PTH values do not predispose to hip fractures. It is interesting that the patients who had PTH values between 196 and 500 pg/dL showed a greater probability of fracture than the group with PTH values greater than 500 pg/dL. This group probably represents a mixture of adynamic bone disease and hyperparathyroid bone disease,32 thus resulting in a greater fracture rate than the group with almost certain hyperparathy-
COCO AND RUSH
roid bone disease. Histologically, very low PTH levels correlated well with adynamic bone disease,14,15,32 which theoretically predisposes to bone fractures in renal osteodystrophy.15,32 It therefore is possible that oversuppression of PTH, resulting in adynamic bone disease, may predispose to hip fractures in dialysis patients. Other studies found a correlation between vertebral fractures and low PTH values in dialysis patients.18,19 Serum aluminum levels were not significantly different in the fracture versus nonfracture groups and did not correlate with occurrence of hip fracture. However, because bone biopsies were not systematically performed, we cannot exclude a contribution from aluminum bone disease. Diabetes mellitus may also affect bone histological characteristics, giving rise to adynamic bone disease.15,33 Patients with diabetes composed 38% of our fracture population, similar to the reference dialysis population. There was no significant difference in cause of ESRD between the fracture and nonfracture groups; therefore, it is unlikely that diabetes mellitus was a major factor predisposing to fractures in the dialysis population. By life-table analysis, we show that survival rate may be influenced by average PTH levels. Lower PTH levels predispose to early mortality in the general dialysis population. A correlation between low PTH level at the start of renal replacement therapy and subsequent early mortality has been reported.34 The duration of dialysis in the entire cohort of patients who sustained hip fractures was not significantly longer than that in the reference dialysis population In this regard, no relation between duration of dialysis therapy and vertebral fracture rate in the Japanese male dialysis patient was found.21 A review of the patients’ chemistry test results showed no significant difference among the groups for calcium, ionized calcium, and aluminum levels. In addition, when the fracture incidence was compared over time, a similar incidence was found in the first half of the decade compared with the second half. In summary, we have shown that the incidence of hip fractures in a dialysis population is alarmingly high compared with that in the general population. The high incidence of hip fractures in patients with ESRD correlates with low PTH
HIP FRACTURES AND LOW PTH
values and likely adynamic bone disease. Oneyear mortality after hip fracture is greater in dialysis patients compared with dialysis patients without hip fracture and greater than that reported in the general population with hip fracture. Our data indicate that survival of patients with ESRD may also be adversely influenced by lower serum PTH levels. These findings suggest that the current practice of aggressive suppression of PTH may need to be revisited. Further studies are necessary to determine the optimum therapy of bone disease in the patient with ESRD. REFERENCES 1. Kellie S, Brody J: Sex-specific and race-specific hip fracture rates. Am J Public Health 80:326-328, 1990 2. Samsioe G: Osteoporosis—An update. Acta Obstet Gynecol Scand 76:189-199, 1997 3. Lindsay R, Cosman F: Primary osteoporosis, in Coe F, Favus M (eds): Disorders of Bone and Mineral Metabolism. New York, NY, Raven, 1992, pp 831-837 4. Jones D, Koval K, Zuckerman J, Aharonoff G, Skrovon M: Epidemiology, in Koval KJ, Zuckerman JD (eds): Fractures in the Elderly. Philadelphia, PA, LippincottRaven, 1998, pp 3-9 5. Melton L, Therneau T, Larson D: Long-term trends in hip fracture prevalence: The influence of hip fracture incidence and survival. Osteoporos Int 8:68-74, 1998 6. Tucci, J: Osteoporosis update. Med Health 81:169173, 1998 7. Prestwood KM, Kenny AM: Osteoporosis: Pathogenesis, diagnosis, and treatment in older adults. Clin Geriatr Med 14:577-599, 1998 8. Farmer M, White L, Brody J, Bailey K: Race and sex differences in hip fracture incidence. Am J Public Health 74:1374-1380, 1984 9. Villa ML, Nelson L: Race, ethnicity, and osteoporosis, in Osteoporosis. San Diego, CA, Academic, 1996, pp 435447 10. Cummings S, Browner W, Bauer D, Stone K, Ensrud K, Jamal S, Ettinger B: Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med 339:733-738, 1998 11. Slemenda C: Prevention of hip fractures: Risk factor modifications. Am J Med 103:S65-S73, 1997 (suppl 2A) 12. Sherrard D, Hercz G, Pei Y, Maloney NA, Greenwood C, Manuel A, Saiphoo C, Fenton SS, Segre GV: The spectrum of bone disease in end-stage renal failure—An evolving disorder. Kidney Int 43:436-442, 1993 13. Indridson O, Quarles L: Prevention and management of renal osteodystrophy in dialysis patients, in Bushinsky D (ed): Renal Osteodystrophy. Philadelphia, PA, LippincottRaven, 1998, pp 445-472 14. Sherrard D: Low turnover renal osteodystrophy, in Bushinsky D (ed): Renal Osteodystrophy. Philadelphia, PA, Lippincott-Raven, 1998, pp 305-316 15. Malluche H, Monier-Faugere MC: Risk of adynamic
1121
bone disease in dialyzed patients. Kidney Int 42:S62-S67, 1992 (suppl 38) 16. Sherrard D: Aluminum and renal osteodystrophy. Semin Nephrol 6:5-11, 1986 17. Pierides A, Edwards W, Cullum U, McCall J, Ellis H: Hemodialysis encephalopathy with osteomalacic fractures and muscle weakness. Kidney Int 18:115-124, 1980 18. Atsumi K, Kushida K, Yamazaki K, Shimizu S, Ohmura A, Inoue T: Risk factors for vertebral fractures in renal osteodystrophy. Am J Kidney Dis 33:287-293, 1999 19. Piraino B, Chen T, Cooperstein L, Segre G, Puschett J: Fracture and vertebral bone mineral density in patients with renal osteodystrophy. Clin Nephrol 30:57-62, 1988 20. Kohlmeier M, Saupe J, Shearer M, Schaefer K, Asmus G: Bone health of adult hemodialysis patients is related to vitamin K status. Kidney Int 51:1218-1221, 1997 21. Kohlmeier M, Saupe J, Schaefer K, Asmus G: Bone fracture history and prospective bone fracture risk of hemodialysis patients are related to apolipoprotein E genotype. Calcif Tissue Int 62:278-281, 1998 22. Gupta A, Kallenbach L, Divine G: Increased risk of hip fractures in US Medicare end-stage renal disease (ESRD) patients. J Am Soc Nephrol 8:552A, 1977 (abstr) 23. Gardner M, Altman D: Statistics with confidence. BMJ 59-60, 1989 24. Ingelfinger J, Mosteller F, Thibodeau L, Ware J: Biostatistics in Clinical Medicine. New York, NY, Macmillan, 1983 25. Cooper C: Southampton, United Kingdom: The crippling consequences of fractures and their impact on quality of life. Am J Med 103:S12-S19, 1997 (suppl 2A) 26. Grisso JA, Kelsey JL, Strom BL, O’Brien LA, Maislin G, LaPann K, Samelson L, Hoffman S, and The Northeast Hip Fracture Study Group: Risk factors for hip fracture in black women. N Engl J Med 330:1555-1560, 1994 27. Lips P: Amsterdam, The Netherlands: Epidemiology and predictors of fractures associated with osteoporosis. Am J Med 103:S3-S11, 1997 (suppl 2A) 28. Cooper C, Melton LJ: Magnitude and impact of osteoporosis and fractures, in Osteoporosis. San Diego, CA, 1996, pp 419-434 29. Jacobsen SJ, Goldberg J, Miles TP, Brody J, Stiers W, Rimm AA: Race and sex differences in mortality following fracture of the hip. Am J Public Health 82:1147-1150, 1992 30. Villa M: Ethnicity and skeletal health, in Marcus R (ed): Osteoporosis. Cambridge, MA, Blackwell Scientific, 1994, pp 125-145 31. Centers for Disease Control and Prevention: Report of the Surgeon General, US Department of Health and Human Services. CDC, Atlanta, GA, 1996 32. Qi Q, Faugere M, Geng Z, Malluche H: Predictive values of serum parathyroid hormone levels for bone turnover in patients on chronic maintenance dialysis. Am J Kidney Dis 26:622-631, 1995 33. Pei Y, Hercz G, Greenwood C, Segre G, Manuel A, Saiphoo C, Fenton S, Sherrard D: Renal osteodystrophy in diabetic patients. Kidney Int 44:159-164, 1993 34. Avram MM, Sreedhara R, Avram DK, Muchnick RA, Fein P: Enrollment parathyroid hormone level is a new marker of survival in hemodialysis and peritoneal dialysis therapy for uremia. Am J Kidney Dis 28:924-930, 1996